Akt and 14-3-3 Control a PACS-2 Homeostatic Switch that Integrates Membrane Traffic with TRAIL-Induced Apoptosis
| Autor: | Matthew H. Brush, Huihong You, Douglas N. Runckel, Joseph E. Aslan, Robert T. Youker, Laurel Thomas, Robert L. Milewski, Arndt Vogel, Jessica Endig, Hongjun Shu, Gary Thomas, Danielle M. Williamson, Haian Fu, Kam Sprott, Kenneth D. Greis, Yuhong Du, Anthony Possemato |
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| Rok vydání: | 2009 |
| Předmět: |
endocrine system diseases
Recombinant Fusion Proteins education Vesicular Transport Proteins Cellular homeostasis Apoptosis Article TNF-Related Apoptosis-Inducing Ligand Mice 03 medical and health sciences 0302 clinical medicine In vivo Cell Line Tumor Neoplasms health services administration Serine Animals Homeostasis Humans Molecular Biology Protein kinase B Cells Cultured Caspase 030304 developmental biology Mice Knockout 0303 health sciences biology Kinase Effector Cell Membrane food and beverages Cell Biology Fibroblasts humanities 3. Good health Cell biology 14-3-3 Proteins Caspases 030220 oncology & carcinogenesis Cancer cell biology.protein Phosphorylation Proto-Oncogene Proteins c-akt BH3 Interacting Domain Death Agonist Protein |
| Zdroj: | Molecular Cell. 34:497-509 |
| ISSN: | 1097-2765 |
| Popis: | TRAIL selectively kills diseased cells in vivo, spurring interest in this death ligand as a potential therapeutic. However, many cancer cells are resistant to TRAIL, suggesting the mechanism mediating TRAIL-induced apoptosis is complex. Here we identify PACS-2 as an essential TRAIL effector, required for killing tumor cells in vitro and virally infected hepatocytes in vivo. PACS-2 is phosphorylated at Ser437 in vivo, and pharmacologic and genetic studies demonstrate Akt is an in vivo Ser437 kinase. Akt cooperates with 14-3-3 to regulate the homeostatic and apoptotic properties of PACS-2 that mediate TRAIL action. Phosphorylated Ser437 binds 14-3-3 with high affinity, which represses PACS-2 apoptotic activity and is required for PACS-2 to mediate trafficking of membrane cargo. TRAIL triggers dephosphorylation of Ser437, reprogramming PACS-2 to promote apoptosis. Together, these studies identify the phosphorylation state of PACS-2 Ser437 as a molecular switch that integrates cellular homeostasis with TRAIL-induced apoptosis. |
| Databáze: | OpenAIRE |
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